DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.

Autor:	Chen P; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Liu Z; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Zhang Q; School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China., Lin D; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Song L; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China., Liu J; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China., Jiao HF; School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China., Lai X; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Zou S; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Wang S; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Zhou T; School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China., Li BM; School of Life Sciences, Nanchang University, Nanchang, 330031, China.; Institute of Life Science, Nanchang University, Nanchang, 330031, China.; School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China., Zhu L; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China fek@ncu.edu.cn panbingxing@ncu.edu.cn zhuli@ibp.ac.cn., Pan BX; School of Life Sciences, Nanchang University, Nanchang, 330031, China fek@ncu.edu.cn panbingxing@ncu.edu.cn zhuli@ibp.ac.cn.; Institute of Life Science, Nanchang University, Nanchang, 330031, China., Fei E; School of Life Sciences, Nanchang University, Nanchang, 330031, China fek@ncu.edu.cn panbingxing@ncu.edu.cn zhuli@ibp.ac.cn.; Institute of Life Science, Nanchang University, Nanchang, 330031, China.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Jan 26; Vol. 42 (4), pp. 532-551. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1523/JNEUROSCI.1003-21.2021
Abstrakt:	Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs. SIGNIFICANCE STATEMENT DSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1β interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism. (Copyright © 2022 Chen et al.)
Databáze:	MEDLINE
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